2-AMINO OR METHYL SULFONYL-6-AMINO SULFONYL OR MILKY SULFONYL-4,8-DIPIPERIDINO OR MORPHOLINOPYRIMIDO{8 5,4-d{9 {11 PYRIMIDINES

ABSTRACT

This invention relates to a novel pyrimido(5,4-d)-pyrimidine derivative having sulfonyl groups or a sulfonyl group substituted by a substituted or non-substituted amino group or an alkyl group at the 2- and/or 6-position. The pyrimidine derivative is useful as a platelet aggregation inhibiting agent.

lJite-l States atent Murakami et al.

[ Aug. 29, 1972 [72] Inventors: Masuo Murakami, No. 19-1-502, Sengoku 2-chome, Bunkyo-ku; Shigemi Kawahara, No. 1970-27, Kurumemachi Minamisawa, Kitatama-gun; Noriyoshi Inukai, No. 43-5, Sengoku Z-chome, Buny-ku, all of Tokyo; Sanae Ishida, No. 1-8, Motobuto 2-chome, Urawa-shi; Kazuo Imai, No. 1314, Nishincho 2- chome, Omiya-shi, both of Saitama; Teruaki Ozasa, No. 16-1, Hasune 3- chome, Itabashi-ku, Tokyo, all of Japan 22 Filed: Nov. 20, 1969 21 Appl.No.: 878,527

[52] US. Cl. ..260/246 B, 260/2565 R, 424/248 [51] Int. Cl. ..C07d 87/46 [58] Field of Search ..260/256.5 R, 246 B, 247.1

[56] References Cited UNITEDSTATES PATENTS Primary Examiner-Alex Mazel Assistant Examiner-Jose Tovar Attorney-Wenderoth, Lind & Ponack [57] ABSTRACT This invention relates to a novel pyrimido[5,4-d]- pyrimidine derivative having sulfonyl groups or a sulfonyl group substituted by a substituted or non-substituted amino group or an alkyl group at the 2- and/or 6-position. The pyrimidine derivative is useful as a platelet aggregation inhibiting agent.

10 Claims, No Drawings Fischer et al. ..260/247.5

As the compounds similar to the compounds of the. preset invention, there are known 2,6- bis(diethanolamino)-4,8-dipendinopyrimido[5,4- d]pyrimidine (generally known as Dipyridamole),

in a solvent such as dioxane, benzene dimethylformamide and the like at room temperature or under cooling, the compound III is prepared. The compound III thus prepared is mixed, with or without being isolated, with about 2 moles of amine and the mixture is reacted at an elevated temperature, preferably at a temperature lower than 150C to provide the compound I. By employing difl'erent amines in the last step and the second step of the above reaction course, different amines can 2,6-bis(ethylmercapto)-4,8-dipiperidinopyrimido-[5,4- 0 be introduced to the 2- and the 6-positions.

d]pyrimidine and the like showing remarkable coronary vasodilatory activity (see; e.g., German Pat. No. 1,116,676; US. Pat. No. 3,031,450; and British Pat. No. 807,826).

Among these known compounds, for example,

ing platelet aggregation. However, it has been found that the compounds of the present invention have an excellent platelet aggregation inhibiting action as compared with these known compounds. Moreover, some of the compounds of this invention can be employed as the raw materials for producing Dipyridamole.

The compound of the present invention may be prepared by reacting pyrimido[5,4-d]pyrimidi.ne substituted with a halogen atom and/or a halogenosulfonyl The compound of the present invention having alkylsulfonyl groups at the 2- and 6-positions may be obtained by reacting the starting material having chlorine atoms at the 4- and 8-positions and a heterocyclic amine, whereby the chlorine atoms thereof are substituted with said amines.

In addition, when a liquid amine is employed in the reaction, a large amount of the liquid amine is employed to utilize a part of the liquid amine as the reaction solvent.

Examples of the compounds of the present invention are shown below:

5 piperidinopyrimidolii,4-d]pyrimidine:

group and an amine to replace the halogen atom or the N CHZOHQOH halogen atom of the halogenosulfonyl group with the amine. T O

The preparation of the compound of the present in- HaCHNOzSFK N CHCHZ H vention will be explained by referring to the-typical N starting material, 2-chloro-6-chlorosulfonylpyrimido[ N 5,4-d]pyrimidine derivative.

The reaction is shown by the following reaction formula: W I

R R; R

I N Ra N\ Cl HN\ (elevated temp.) W 12 N/ I R4 \R I clots-k N R: k5 3N N \NO2S/ N It It (11) Ra Ra (I) HN/ HN/ N N -01 R1=R2-N Ra R4 N N02S N R4 V M i m wherein R, R R R and R have the meaning previ- (2) 2-diethanolamino-6-ethylaminosulf0nyl-4,8-dipiously defined. peridinopyrimido[5,4-d1pyrimidine:

That is, one mole of the starting material 11 is caused to react with more than 4 moles of an amine at an elevated temperature to provide the compound I.

The compound I may be also obtained through the reaction course II III I. That is, by reacting 1 mole of the starting material II and about 2 moles of an amine CHzCHzOH (l1) 2-diethanolaminosulfonyl-6-methylsulf0nyl-4,8- dipiperidinopyrimido [5,4-d1pyrimidine:

CHzCHzOH The following experiments and the results show the excellent medical effects of the compounds of the present invention.

Platelet aggregation inhibiting effect:

The effect of the compounds of the present invention for inhibiting the platelet aggregation caused by adenosine phosphate was compared with that by Dipyridamole.

Experimental procedure:

The blood recovered from the heart of a rat was mixed with a 3.8 percent sodium citrate solution so that the citrate was present in the blood in an amount of 1 /l0 volume part of the blood and the mixture was subjected to a centrifugal separation for minutes at 1,000 rpm. to provide a platelet rich plasma 30 (hereinafter the plasma is called PRP).

To 2.5 ml. of PRP were added 10' mole of adenosine diphosphate, 10- mole of the compound of this invention shown by the below-showing general formula, 7 X 10 mole of sodium chloride, 1.2 X 10' mole of potassium chloride and 9 X l0" mole of calcium chloride to provide a total volume of 5 ml.

While vigorously stirring the mixture at 25C. by means of a thermo-mixed, the extent of the reduction of extinction coefficient caused by the aggregation of platelet was measured every seconds by means of a photoelectric photometer EPO-B (filter 61) made by Hitachi, Ltd. The measurement of the extinction coefficient was made by taking the case of adding no compound of the present invention as the standard.

The extinction coefficient of the system reached the minimum value after l-2 minutes from the start of measurement and was constant for about 5 minutes after then, the value in the period was measured. From the extinction coefiicient thus obtained was calculated the platelet aggregation inhibiting rate (percent) and also the relative value thereof to that of the case of using Dipyridamole instead of the compound of this invention was also calculated, the results of which are shown in table I.

In addition, the devices used in the experiments that might possibly be brought into contact with platelets had been subjected to silicone treatment.

The compounds of the present invention used in the experiments are represented by the following general formula:

N Ih-(hsi TABLE 1 Compound Inhibiting Test ratio Inhibition No. R1 R2 (percent) ratio 1.. NIICII; CHzCHzOII 26 1. 24

CHzCHzOH 2. NHCzHs CII2CII2OII 26 1. 24

OH CHZOH 3 C2H5 /CIIzCHz0H 44 Z. 09

NHCHzCHzN N\ C2 5 CHzCHzOH 4 CHzCHzOH CHzCHzOII 47 .2. 24

CHzCHzOI-I CHzCHzOI-I 5. CH3 CHZCH2OH 20 1. 37

CHzCHzOH CIIzCHzOH 6. \O CIIZCIIZOII 38 1.81

\ CI-IzCHzO II TAB LE 1 Continued Compound Inhibiting Test ratio Inhibition N 0. R1 R2 (percent) ratio 7.-- CH1 CH; 35 1.61

CHzCHzOH CHzCHzOH 8 /CH; CHzCHzOH 27 1.28

CH; CHzCHzO N 9. Dipyridamole 21 1.

In addition; since the lch'owfiompofind, 2,6-bis (ethylmercapto)-4,8-dipiperidinopyrimido[5,4-d] was insoluble in water, the platelet aggregation inhibiting effect by the compound could not be observed.

Now, the invention will be explained by the following examples but the invention shall not be limited to them.

a. Into a suspension of 0.8 g. of 2-chloro-6-mercapto- 4,8-dipiperidinopyrimidol5,4-d]pyrimidine in 25 ml of methanol-water (1:4), chlorine gas was introduced for 1 hour with stirring and cooling to 4 to 5C. The reaction product which was precipitated out was collected by filtration, washed with water and dried. The crude 2- chloro-6-chlor0sulfonyl-4 8-dipiperidinopyrimido[ 5 ,4- d]pyrimidine was chromatographed on a silica-gel column using chloroform as eluent to provide 0.66 g (70 percent) of the product, melting at 228-230C.

b. A solution of 4.3 g of 2-chloro-6-chlorosulfonyl- 4,8-dipiperidinopyrimido[5,4-d]pyrimidine prepared as above in 40 ml of chloroform was added dropwise to a solution of 2.5 g of diethanolamine in 30 ml of chloroform while stirring. After stirring for half an hour, the reaction mixture was washed with water and dried over anhydrous magnesium sulfate. The residue which was obtained by removal of the solvent was chromatographed on a silica-gel column using benzene and then ethyl acetate as eluents. The effluent was concentrated under reduced pressure to provide 3.7 g (74.6 percent) of 2-ch1oro-6-diethanolamino-su1fonyl-4,8-

dipiperidinopyrimido[5,4-d1pyrimidine, melting at 1 68C.

Analysis c,,1-1,,N,0.sc1

C(%) H( N(%) calcd. 48.04 6.05 19.61 found 48.09 6.15 19.58

The following compounds shown by general formula were obtained by proceeding in a manner analogous to that described lzevalzat i as fi eet a N Iii-02S 41 Elementary analysis (percent) Calcd. Found 11.1. Yield R1 C.) (percent) C II N C H N 208-210 67 53.57 6.54 19.84 53. 48 6.51 19.80 HN- H NHCH 203-205 70.6 47.03 5.68 23.02 47.00 5.71 23.12 NHC H 150-161 55.2 50.27 6.22 21.60 50.30 6.31 21.48

NHC1H9 131-132 64.0 51.33 6.46 20.05 51.61 6.38 20.03

CH2CH2OH 168 74.6 48.04 6.05 10.61 48.00 6.15 10.58

CHzCHzOH CzHs 112-115 51.70 6.00 21.03 51.70 6.70 21.74

NHCH2CH2N Table Continued Elementary analysis (percent) Calcd. Found Ml. Yield R C.) (percent) C H N C H N CHzCHzOH CZHS EXAMPLE 1 then the solvent was removed by evaporation. The ob- Z-diethanolamino-6-diethanolaminosulfonyl-4,8- dipiperidinopyrimido[5,4-d1pyrimidine:

Into a solution of 1.5 g of 2-chloro-6- diethanolaminosulfonyli,8-dipiperidinopyrimido[5,4-

dlpyrimidine prepared as above in 30 ml of dioxane oily substance, which was dissolved in ml of 25 chloroform. The chloroform solution was washed with water and dried over anhydrous sodium sulfate, and

W 111-0. sk 4I tained residue was chromatographed on a silica gel column using ethyl acetate as eluent. The eflluent was concentrated under reduced pressure to provide 1.3 g (76.5 percent) of product, melting at l-l4l .5C.

Analysis c n uos H( N(%) calcd. 50.69 7.09 l9.70 found 50.50 7.08 19.71

Calcd Found Yield Rl R M.P. C.) (percent) C H N C H N (HzCHzUIl' 185-18 78 55. 40 .52 10.02 55.2 7 NH H H I I 0 I. 53 1.|. l5

CH2CHZOH .NHCH /('112CH201I 153-155 76.2 50. 0!! 6.03 22.65 51.01 7.00 22.

CH1CH2OH NHC HT CHzCHzOH 180. 5-187. 5 04. 8 52. 7. 33 21. 4-1 52. 5!] 7. 40 21.17

CHzCHzOH /C 31211 /C H CH OH 122-124 74. 5 55. 30 7. 85 10. 81 55. 38 7. 87 10. 66 \Z C3117 CHzCHzOH NHC4H9 CHzCHzOH -167 82 53. 71 7. 51 '20. 88 53. 58 7. 73 '20. 46

\ CHzCHrOH /CHzCHzOH CHzCHzOH (I-141.5 76.5 50. 61 7.03 19.68 50.50 7. 08 10.71 -N N CHzCHzOI-I CHzCHzOH Table-Continued Elementary analysis (percent) Calcd. Yield Found R R, M1. 0.) (percent) C H N C II N C 115 CI'IgC 11 011 ALB-101.5 V 75 53.86 7. 82 21.74 53.48 7.88 21.52 -Nncrncnm N\ CzHs CHzCHzOH CH: /CH2CH2OH 109-100. 38 51. 28 7.11. 20. 80 51. 3O 7. 01 20. 73

CHzCHzOH OHzCHzOH EXAMPLE 2 column using ethyl acetate as eluent. The effluent was 2-diethanolamino-6-diethylaminosulfonyl-4,8- dipiperidino-pyrimido[5,4-d]pyrimidine:

A solution of 0.86 g of 2-chloro-6-chlorosulfonyl-4,8 -dipiperidinopyrimido[5,4-d1pyrimidine in 20 ml of benzene was added to a solution of 1.4 g of diethylamine in 30 ml of benzene while stirring at room concentrated under reduced pressure to provide 0.44 g (41.4 percent) of pure product, melting at l l8l 20C.

Analysis C H N O S C(%) H(%) N( calcd. 53.71 7.51 20.88 found 53.83 7.59 20.69

Elementary analysis (percent) Cnlcd. Found M. 1. Yield R; Rz 0.) (percent) 0 II N C H N CH CH 011 0'1 1. 2 NHCH2CH2 2 2 l 4 3 67 5 6 J0 18.8 57. 05 7.00 18.53

C H2O H: OH

N/ CHzCHzOH 160-162 48. 6 52. 6. 96 20. 35 52. 05 6. 87 20. 12

\ CHzCHzO H /CH: CHzCHzOH 143 29 51.95 7.13 22.03 51.99 7.22 21.82 -N CH3 CHzC HzoH -NHC2H5 CHzCHzOI-I 164-165 39. 0 51.95 7. 13 22. 03 52. 16 7.17 21.

CHzCHgOH /C4H| CHzCHzOH 108-110 55. 6 56. 73 8. 16 18. 56. 88 8. 21 18. 74 N -N C 4H CHzCHzOH N/ /CH2CH2OH 141-143 59. 5 54. 72 7. 35 20. 42 55. 08 7. 40 20. 29

The starting material was prepared as follows:

To a solution of 3.0 g of 2-ch1oro-6-chlorosulfonyl- 4,8-dimorpholinopyrimido[5,4-d]pyrimidine in 60 ml of benzene was added a solution of 3.06 g of dibutylamine in 30 ml of benzene while stirring. After stirring 2 hours, the benzene was distilled off under reduced pressure. The residue was dissolved in chloroform. The chloroform solution was washed with water and dried over anhydrous magnesium sulfate, and then the solvent was removed by evaporation. The residue was recrystallized from ethanol-chloroform to provide 2.55 g (70 percent) of 2-chloro-6-dibutylaminosulfonyl-4,8-dimorpholinopyrimido[5,4-d]- pyrimidine product, melting at l48l49C.

Analysis C H N-,O SCI C(%) H(%) N(%) calcd. 50.05 6.49 18.57 found 49.91 6.32 18.64

EXAMPLE 3 Analysis C H N O S c H(%) calcd. 52.33 7.54 18.78 found 51.80 7.46 18.57

EXAMPLE 4 2-diethan01amino-6-diethylaminosulfonyl-4,8- dimorpholinopyrimido[5,4-d]pyrimidine:

A solution'of 3.0 g of 2-chloro-6-chlorosulfonyl-4,8- dimorpholinopyrimido[5,4-d]pyrimidine in 60 ml of benzene was added to a solution of 1.8 g of diethylamine in 20 ml of benzene while stirring at room temperature. After stirring for 2 hours, the benzene was distilled off under reduced pressure. The residue was dissolved in chloroform. The chloroform solution was washed with water and dried over anhydrous magnesium sulfate, and then the solvent was removed by evaporation. To the obtained residue was added 25 ml of diethanolamine and the mixture was heated to 160C for half an hour. The reaction mixture was dissolved in 50 ml of chloroform washed with water and dried over anhydrous magnesium sulfate and then the solvent was removed by evaporation. The obtained residue crystallizes with the addition of a small amount of petroleum ether and recrystallized from ethylacetate-petroleum ether to provide 2.1 g (52.5 percent) of product, melting at 100C.

N( calcd. 48.88 6.71 20.73 found 48.71 6.72 20.36

EXAMPLE 5 2-(N-methyl)ethanolarnino-6-(N- methyl)ethanolamino-sulfonyl-4,8- dipiperidinopyrimido[5,4-d]pyrimidine:

To a solution of 1.5 g of 2-chloro-6-chlorosulfonyl- 4,8-dipiperidinopyrimido[5,4-d]pyrimidine in 50 ml of benzene w as added 2.63 g of N-methylethanolamine in 10 ml of benzene while stirring. After stirring for 2 hours, the benzene was distilled off under reduced pressure. The residue was dissolved in chloroform, washed with water, dried over anhydrous magnesium sulfate and then the solvent was removed by evaporation. The obtained residue was chromatographed on a silica-gel column using ethyl acetate as eluent. The effluent was concentrated under reduced pressure and the obtained residue was recrystallized from ethyl acetate petroleum ether to provide 0.5 g (42 percent) of product, melting at l 15C.

Analysis C H N O S calcd. 51.95 7.13 22.03 found 51.70 7.08 22.03

The following compounds shown by general formula were obtained by proceeding in a manner analogous to that described above, but using different amines.

N I R2 Reels-L N Elementary analysis (percent) Yield Caled. Found M.P. (por- R1= Rz= 0.) cent) C II N C H N NIICH3 193-194 35 51. 43 6. 67 26. 67 51. 19 6. 57 26. 44

The starting material was prepared as follows:

a. A mixture of 4g of 4,8-dihydroxy-2,-dimercaptopyrimido[5,4-d1pyrimidine, 22 g of phosphorous pentachloride and m1 of phosphorous oxychloride was refluxed by heating in an oil bath for 30 minutes. The reaction mixture was concentrated under reduced pressure to give the residue, from which excess phosphorous pentachloride was sublimated as thoroughly as possible at about 70C under reduced 4,8-dichloro-2,6-bis(chlorosulfeno)pyrimido [5,4-dlpyrimidine was precipitated out by the addition of 5 ml of chloroform to the residue, which was collected by filtration. The yield was 5.1 g (87 percent), melting point l98199C.

Analysis C N,S Cl

C(%) N(%) Cl(%) S(%) calcd. 21.67 16.77 42.48 19.20 found 21.57 16.57 42.05 19.40

b. To a solution of 350 mg of 4,8-dichloro-2,6- bis(chlorosulfeno)pyrimido[5,4-d]pyrimidine obtained as above in 10 ml of a dry dioxane was added dropwise 0.8 ml of piperidine with stirring and cooling. The reaction mixture was stirred at room temperature for 1 hour and at 50C for 30 minutes, and then concentrated. The residue was dissolved in 50 ml of chloroform and the solution was washed three times with 10 ml each of water. After the solution was dried over anhydrous sodium sulfate, the chloroform was removed by evaporation under reduced pressure. The reaction product was precipitated out as crystals by the addition of 1 to 2 ml of ethyl acetate to the obtained residue. The crystals were collected by filtration, washed with a small amount of ethyl acetate and dried to give 370 mg (67 percent) of 4,8-dipiperidino-2,6-bis(piperidinosulfeno)pyrimido[5,4-d]-pyrimidine, melting at 165-167 O Analysis C H N S,

C(%) H(%) N(%) S(%) calcd. 59.06 7.62 21.19 12.13 found 58.90 7.36 20.76 11.86

c. Into a suspension of 100 mg of 4,8-dipiperidino- 2,6-bis(piperidinosulfeno)pyrimido[5,4-d]pyrimidine in 7 ml of water-methanol (:2) mixture was introduced chlorine gas for 2 hours while stirring and icecooling. The resulting yellow crystals were collected by filtration, washed with water and dissolved in 50 ml of chloroform. The thus obtained solution was successively washed three times with 10 ml of 3 percent aqueous sodium bicarbonate, three times with 10 ml each of water and dried over anhydrous sodium sulfate. From the solution, the crude product was obtained as crystals by evaporation of the chloroform under reduced pressure, collected by filtration and washed with a small amount of ethyl acetate to give 90 mg (96 percent) of 2,6-bis(chlorosulfonyl)-4,8-dipiperidinopyrimido-[4,8- d]pyrimidine.

Analysis c,,11,,N,s,o,c|,

N(%) S(% Cl(%) calcd. 38.79 4.07 16.96 12.94 14.31 found 39.29 4.46 16.39 12.49 14.05

EXAMPLE6 2,6-bis(diethanolaminosulfonyl)-4,8-dipiperidinopyrimido[5,4-d]pyrimidine:

Into a solution of 100 mg of 2,6-bis(chlorosulfonyl)- 4,8-dipiperidinopyrimido[5,4-d]pyrimidine in a dry dioxane was added 85 mg of diethanolamine with stirring and cooling. Additional stirring was continued for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in chloroform and the obtained solution was successively washed once with water, twice with l N aqueous hydrochloric acid, twice with 5 percent aqueous sodium bicarbonate, three times with water and dried over anhydrous sodium sulfate. From the solution, the chloroform was removed by evaporation under reduced pressure. The thus obtained light yellow oily substance was dissolved in a small amount of chloroform and purified by column chromatography on silica-gel using chloroform-methanol (13:1) mixture as eluent.

The colorless or light yellow oily substance which was obtained by concentration of the effluent was allowed to stand at room temperature. The obtained white needle product was collected by filtration and washed with a small amount of ethyl acetate. The yield of the product, having a melting point of 107-l12C (decomposition) was mg (63 percent).

Analysis Cg4H NaO5Sg C( calcd. 45.56 6.37 17.71 10.13 found 45.23 6.26 17.42 9.97

EXAMPLE 7 Analysis: C H N ClO S,

C(%) H(%) N( calcd. 42.99 4.88 17.69 found 43.23 5.09 17.42

A solution of 1.4 g of 2-chlorosulfonyl-6-methyl-sulfonyl-4,8-dipiperidino-pyrimido[5,4-d]pyrimidine in 10 ml of chloroform was added dropwise into a solution of 0.95 g of diethanolamine in 20 ml of chloroform while stirring. After additionally stirring for 1 hour, the reaction mixture was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The oily residue was poured into water and allowed to stand overnight, whereby the reaction product was solidified. The crude product was collected by filtration and recrystallized from ethyl acetate to give 1.45 G (89.7 percent) of product, melting at 152153C.

Analysis C: H ,N-,O S,

C(%) H(%) calcd. 46.39 6.12 18.03 found 46.17 6.14 l7.96

EXAMPLE 8 2,6-bis(methylsulfonyl)-4,8-dipiperidinopyrimido [5,4-d]-pyrimidine.

The starting material was prepared as follows:

a. mixture of 2.9 g of 4,8-dihydroxy-6-mercapto-2- methylthiopyrimido[5,4-d]pyrimidine and 33 ml of 5 percent sodium hydroxide was warmed, until a clear melt had formed. After cooling, 0.9 ml of methyl iodide was added to the reaction mixture while vigorously stirring to precipitate a crude 4,8-dihydroxy-2,6- bis(methylthio)-pyrimido[5,4-d]pyrimidine as yellow crystals. After additional stirring was continued for 30 Analysis C H N,O,S,

C(%) H(%) N(%) calcd. 37.49 3.15 21.86 found 37.30 3.22 21.94

b. into a suspension of 6.4 g of 4,8-dihydroxy-2,6- dimethylthiopyrimido[5,4-d]pyrimidine prepared as above in 320 ml of water was introduced chlorine gas at to C while stirring, whereby crude crystals were precipitated out. After standing for a while, the crystals were collected by filtration and washed with water to give 7.6 g (95 percent) of crude 4,8-dihydroxy-2,6- bis( methylsulfonyl)pyrimido[h l 5 ,4-d]pyrimidine. The

crude product was dissolved in dilute aqueous ammonia and the solution was treated with charcoal, and then the PH thereof was adjusted to 4 by the addition of acetic acid, whereby the product was reprecipitated. The product was collected by filtration to yield the pure product.

Analysis C H N O S,

N(%) S(%) calcd. 18.47 20.02 found 18.29 19.80

c. A mixture of 5.6 g of 4,8-dihydroxy-2,6- bis(methylsulfonyl)pyrimido[h15,4-d]pyrimidine prepared as above, 14.5 g of phosphorus pentachloride and 28 ml of phosphorus oxychloride was heated for l hour while stirring. After the reaction was completed, phosphorus oxychloride was evaporated off under reduced pressure. The residue was extracted with 30 ml of hot chloroform and the extract was cooled. The crude product which was precipitated out was washed with water to give 4.65 g (74.5 percent) of 4,8- dichloro-2,6-bis(methylsulfonyl)pyrimido[5,4-d]- pyrimidine as crystals, melting at 270-272C (decomposition).

N( Cl(%) S(%) calcd. 15.69 19.85 17.93 found 15.52 20.04 17.74

d. To a suspension of 0.36 g of 4,8-dichloro-2,6- bis( methylsulfonyl )pyrimido[h l 5 ,4-d]pyrimidine prepared as above in 3.6 ml of chloroform was added dropwise 0.4 ml of piperidine with stirring, whereby a clear, yellow-brown solution was formed by a slight generation of heat accompanied. After additionally stirring for 30 minutes, the solution was washed twice with water. The chloroform layer was dried over anhydrous sodium sulfate, treated with charcoal and concentrated under reduced pressure to give 0.38 g (83 percent) of the crude 2,6-bis(methylsulfonyl)-4,8- dipiperidinopyrimido[5,4-d]-pyrimidine. On recrystallization from acetone, the fine, light yellow needles, melting at 21 8-220C, were obtained.

Analysis C ,H N,O S,

C(%) H(%) N(%) calcd. 47.56 5.77 18.49 14.08 found 47.49 5.69 18.25 14.10

What is claimed is: l. A pyrimido [5,4-d] pyrimidine derivative represented by the formula 1. A pyrimido [5,4-d] pyrimidine derivative represented by the formula j-(SOz) PR1 N Ill-02S wherein R represents piperidino or morpholino; R and R each represents methyl, piperidino, morpholino or R and R4 each representing amember selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, cyclohexyl, hydroXy-ethyl and diethylamino ethyl; and n is 0 or 1, said R and R each representing on y when n is 0.

2. A compound according to claim 1, namely 2- diethanol-amino-6-diethanolaminosulfonyl-4,8- dipiperidinopyrimido[5,4-d]-pyrimidine.

3. A compound according to claim 1, namely 2- diethanolamino--diethylaminoethylaminosulfonyl-4,8 -dipiperidinopyrimido-[5,4-d1pyrimidine.

4. A compound according to claim 1, namely 2- diethanolaminol6-morpholinosulfonylo4,8- dipiperidinopyrimido[5,4-d]pyrimidine.

5. A compound according to claim 1, namely 2-(N- methyl)ethanolamino-6-(N-methyl)ethanolaminosulfonyl-4,8-dipiperidinopyrimido[5,4-d]pyrimidine.

6. A compound according to claim 1, namely 2- diethanolamino-6-dimethylaminosulfonyl4,8- dipiperidinopyrimido-[5,4-d]pyrimidine.

7. A compound according to claim 1, namely 2- diethanolamino-6-(N-methyl)ethanolaminosulfonyl- 4,8-dipiperidinopyrimido[5,4-d]pyrimidine.

8. A compound according to claim 1, namely 2- diethanolaminosulfonyl-6-methylsulfonyl-4,8- dipiperidinopyrimido-[S,4-d]pyrimidine.

9. A compound according to claim 1, namely 2,6-bis- (diethanolaminosulfonyl)-4,8-dipiperidinopyrimido[ 5,4-d]pyrirnidine.

10. A compound according to claim 1, namely 2,6- bis(methylsulfonyl)-4,8dipiperidinopyrimido[5,4- d]pyrimidine. 

2. A compound according to claim 1, namely 2-diethanol-amino-6-diethanolaminosulfonyl-4,8-dipiperidinopyrimido(5,4-d) -pyrimidine.
 3. A compound according to claim 1, namely 2-diethanolamino-6-diethylaminoethylaminosulfonyl-4,8-dipiperidinopyrimido -(5,4-d)pyrimidine.
 4. A compound according to claim 1, namely 2-diethanolamino16-morpholinosulfonyl-4,8-dipiperidinopyrimido(5,4 -d)pyrimidine.
 5. A compound according to claim 1, namely 2-(N-methyl)ethanolamino-6-(N-methyl)ethanolaminosulfonyl-4,8 -dipiperidinopyrimido(5,4-d)pyrimidine.
 6. A compound according to claim 1, namely 2-diethanolamino-6-dimethylaminosulfonyl4,8-dipiperidinopyrimido-(5,4 -d)pyrimidine.
 7. A compound according to claim 1, namely 2-diethanolamino-6-(N-methyl)ethanolaminosulfonyl-4,8 -dipiperidinopyrimido(5,4-d)pyrimidine.
 8. A compound according to claim 1, namely 2-diethanolaminosulfonyl-6-methylsulfonyl-4,8-dipiperidinopyrimido-(5,4 -d)pyrimidine.
 9. A compound according to claim 1, namely 2,6-bis-(diethanolaminosulfonyl)-4,8-dipiperidinopyrimido(5,4-d)pyrimidine.
 10. A compound according to claim 1, namely 2,6-bis(methylsulfonyl)-4,8-dipiperidinopyrimido(5,4-d)pyrimidine. 